Thrombocyte Regulation of Anti-Parasite Immunity

抗寄生虫免疫的血小板调节

基本信息

批准号：
10056191
负责人：
Alfred LM Bothwell
金额：
$ 41.88万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-11-05 至 2021-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10056191
关键词：
Address Affect Automobile Driving Back Biological Blood Platelets CD4 Positive T Lymphocytes Cell Differentiation process Chemosensitization Chronic Clinical Communicable Diseases Cutaneous Cutaneous Leishmaniasis Cytokine Signaling Data Development Disease Disease Outcome Disease susceptibility Equilibrium Event Failure Genetic Goals Growth Homeostasis Hour Immune Evasion Immune response Immune system Immunity Immunologics Impairment In Vitro Inbred BALB C Mice Infection Infiltration Inflammation Injury Interleukin-10 Interleukin-13 Interleukin-4 Lead Leishmania Leishmania major Leishmaniasis Lesion Leukocytes Ligands LoxP-flanked allele Lymphocyte MYD88 deficiency Measures Mediating Megakaryocytes Molecular Monitor Monoclonal Antibodies Mouse Strains Mus Neutrophil Infiltration Parasites Parasitic Diseases Parasitic infection Pathogenesis Pathologic Pathway interactions Pharmacological Treatment Phase Phenotype Plasmodium falciparum Platelet Activation Process Public Health Regulation Role Route S100A8 gene Schistosoma mansoni Signal Transduction Site Source Sterility Structure Surface Symptoms T-Lymphocyte TLR2 gene Testing Th2 Cells Therapeutic Therapeutic Effect Time Tissues Trypanosoma cruzi Ulcer Virulence Factors Visceral WNT Signaling Pathway adaptive immune response chronic infection chronic inflammatory disease cytokine disease phenotype experimental study healing immunopathology in vivo inhibitor/antagonist insight interleukin-10 receptor macrophage mutant neutrophil novel pathogen peripheral blood receptor reconstitution recruit response therapeutic evaluation therapeutic target therapeutic vaccine therapeutically effective tissue repair

项目摘要

Parasitic infection by Leishmania is a well-known example of a chronic inflammatory disease. Upon infection/injury, leukocytes are recruited to the affected site, and further polarized. The activation of Wnt signaling is possibly one of the initial molecular responses to maintain tissue homeostasis and tissue repair. It is known that platelets are important players in these processes. Although chronic inflammation in parasitic infection is a consequence of constant interaction between the host immune system and parasites, how chronic immune responses are elicited and modulated by parasitic infection remains elusive. The important insight of this proposal is that platelets release significant amounts of the Wnt antagonist Dickkopf-1 (Dkk-1) following parasite recognition and such elevated levels of Dkk-1 regulate multiple levels of the immune response to support chronic inflammation. Consequently, this sequence of events favors parasite survival and constant immunopathology in the host. This systemic increase in Dkk-1 has potent effects on the immune system leading to the development of chronic TH2 immune responses and a potentiation of IL-10. Importantly, CD4 T cells developing under TH1 conditions were driven towards a TH2 (IL-4, IL-13, IL-10) phenotype in the presence of Dkk-1. We propose two aims to examine the interplay between platelets/Dkk-1 at several pivotal points of Leishmania-host innate and adaptive immune responses. In the first aim, the mechanisms by which Dkk-1 is released from platelets will be addressed. As activation is TLR2 dependent, Leishmania mutants that lack characterized surface virulence factors will be utilized. Given the known importance of PMN leukocytes (neutrophils) in Leishmania infection, we will also address the mechanism by which Dkk-1 increases leukocyte-platelet aggregates (LPA) and recruits leukocytes to the infection site. The second aim will specifically probe the consequences of conditional deletion in CD4 T cells of LRP6, the receptor for Dkk-1, and c-Maf and in neutrophils deletion of the receptor for IL-10 and LRP6. The goal is to investigate the contribution of these factors in platelets, CD4 T cells and neutrophils in parasitic infection leading to disease susceptibility or a failure to elicit sterile immunity that results in persistent infection. Taken together, this proposal will provide novel biological insight towards understanding parasitic recognition and evasion during infection and consequent pathogenesis. Our proposal has a primary focus on investigating the mechanism by which overexuberant immune responses are elicited and maintained by host-pathogen interaction. Since we propose multifaceted role(s) of platelet-derived Dkk-1 in modulating immune responses, our study will identify important roles of platelets in leishmaniasis, and contribute to developing Dkk-1 and related biological pathways as effective therapeutic targets in leishmaniasis and potentially other infectious diseases.

利什曼原虫寄生虫感染是慢性炎症性疾病的一个众所周知的例子。之上感染/损伤时，白细胞被募集到受影响的部位，并进一步极化。 Wnt的激活信号传导可能是维持组织稳态和组织修复的初始分子反应之一。它众所周知，血小板在这些过程中发挥着重要作用。尽管寄生虫存在慢性炎症感染是宿主免疫系统和寄生虫之间不断相互作用的结果，如何由寄生虫感染引起和调节的慢性免疫反应仍然难以捉摸。重要的该提议的见解是血小板释放大量的 Wnt 拮抗剂 Dickkopf-1 (Dkk-1) 寄生虫识别后，Dkk-1 水平升高可调节多个水平支持慢性炎症的免疫反应。因此，这一系列事件有利于寄生虫宿主的生存和持续的免疫病理学。 Dkk-1 的系统性增加对免疫系统导致慢性 TH2 免疫反应的发展和 IL-10 的增强。重要的是，在 TH1 条件下发育的 CD4 T 细胞被驱动向 TH2（IL-4、IL-13、IL-10）发展 Dkk-1 存在时的表型。我们提出了两个目标来检查血小板/Dkk-1 之间的相互作用利什曼原虫宿主先天性和适应性免疫反应的几个关键点。在第一个目标中，将讨论 Dkk-1 从血小板中释放的机制。由于激活依赖于 TLR2，将利用缺乏特征表面毒力因子的利什曼原虫突变体。鉴于已知 PMN 白细胞（中性粒细胞）在利什曼原虫感染中的重要性，我们还将通过以下方式解决其机制：其中 Dkk-1 增加白细胞-血小板聚集体 (LPA) 并将白细胞募集到感染部位。这第二个目标将专门探讨 CD4 T 细胞中 LRP6 条件性缺失的后果， Dkk-1 和 c-Maf 受体，以及中性粒细胞中 IL-10 和 LRP6 受体的缺失。目标是研究血小板、CD4 T 细胞和中性粒细胞中这些因素在寄生虫感染中的作用导致疾病易感性或无法引发无菌免疫，从而导致持续感染。采取总之，该提案将为理解寄生识别和感染期间的逃避和随后的发病机制。我们的建议主要集中于调查宿主病原体引发和维持过度旺盛的免疫反应的机制相互作用。由于我们提出血小板衍生的 Dkk-1 在调节免疫反应中的多方面作用，我们的研究将确定血小板在利什曼病中的重要作用，并有助于开发 Dkk-1 和相关的生物途径作为利什曼病和其他潜在传染病的有效治疗靶点疾病。